Alzheimer's disease, namely senile dementia, is the most common neurodegenerative disease leading to dementia in the aged. According to a report by John Hopkins University (US), 1 of 85 people would be living with AD by 2050. The clinical manifestations of AD are progressive loss of memory and cognitive function, decline of daily self-care ability, and emergence of various psychotic symptoms and behavior disorders. The autopsied brain tissue sections of AD victims are characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Wherein, senile plaques are mainly composed of neurotoxic βamyloid (Aβ) peptide, which is proposed to be responsible for AD pathogenesis in the mainstream theory of ‘Amyloid Hypothesis’.
Further, Aβ is generated through a sequential cleavage of Amyloid Precursor Protein (APP) by β- and γ-secretase, while the α-secretase cleavage of APP precludes Aβ formation and produces neurotrophic sAPPα (Mudher, A. & Lovestone, S. Trends Neurosci 25, 22-26 (2002); Selkoe, D. J. Ann Intern Med 140, 627-638 (2004); Selkoe, D. J. Nat Med 17, 1060-1065).
As to the diagnosis of AD, the golden standard of AD diagnosis presently relys on the pathological examination of postmortem brain section from the victims to confirm the existence of extracellular plaques and intracellular tangles. Instead, the clinical diagnosis of AD relys on the examining of cognitive function with tests such as mini-mental state examination (MMSE). However, as a subjective test for diagnostic basis, the specificity and the sensitivity of MMSE are low.
However, an early prediction of AD risk and an early intervention obviously are more clinically valuable than a late diagnosis after cognitive impairment or a postmortem diagnosis.
Therefore, there is an urgent need for the field to develop a sensitive, reliable biomarker suitable for early AD prediction/diagnosis so as to identify high-risk patients objectively and accurately before cognitive impairments happens, predict the possibility of AD at early stage, and provide a time window for the prevention or treatment of AD.
As to the AD treatment, it is known that the regulation of APP cleavage by secretases (such as γ-secretase) for reducing Aβ production can be utilized for AD treatment. However, clinical trials for treating AD by using γ-secretase inhibitor turned out to be unsuccessful. According to the present main view, the failure of the clinical trials was attributed to the diverse substrates of γ-secretase besides APP, such as Notch, E-cadherin and ErbB-4, etc (Haapasalo, A. & Kovacs, D. M. J Alzheimers Dis 25, 3-28; Xia, W. & Wolfe, M. S. J Cell Sci 116, 2839-2844 (2003)). These substrates achieve their important physiological functions through γ-secretase cleavage. Therefore, γ-secretase inhibitors may interfere the nomal physiological functions of many substrates.
Recently, Eli Lily terminated a phase 3 clinical trial of a γ-secretase inhibitor (Semagacestat, LY450139). The clinical result showed that after taking Semagacestat, the cognitive function of the AD patients was declined, and the risk of skin cancer and the adverse gastrointestinal reaction were increased. Wherein, the latter two were considered to be related with the disadvantaged inhibition of γ-secretase cleavage of Notch (Siemers, E., et al. Safety, Clin Neuropharmacol 28, 126-132 (2005); Siemers, E. R., et al. Neurology 66, 602-604 (2006); Hofmann, T., Schaefer, M., Schultz, G. & Gudermann, T. Proc Natl Acad Sci USA 99, 7461-7466 (2002).). This indicated that a desired medication for AD treatment must specifically reduce the γ-secretase cleavage of APP without affecting its function for cleavage of other substrates.
Thus, it's still urgent to develop a medication for treating or preventing AD with fewer side effects.